scholarly journals Future Therapeutic Directions for Smac-Mimetics

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 406 ◽  
Author(s):  
Emma Morrish ◽  
Gabriela Brumatti ◽  
John Silke
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Inhibitor Of Apoptosis ◽  
Growth Strategies ◽  
Promote Tumor Growth ◽  
Cell Death Program ◽  
Smac Mimetics ◽  
Promote Cell Death

It is well accepted that the ability of cancer cells to circumvent the cell death program that untransformed cells are subject to helps promote tumor growth. Strategies designed to reinstate the cell death program in cancer cells have therefore been investigated for decades. Overexpression of members of the Inhibitor of APoptosis (IAP) protein family is one possible mechanism hindering the death of cancer cells. To promote cell death, drugs that mimic natural IAP antagonists, such as second mitochondria-derived activator of caspases (Smac/DIABLO) were developed. Smac-Mimetics (SMs) have entered clinical trials for hematological and solid cancers, unfortunately with variable and limited results so far. This review explores the use of SMs for the treatment of cancer, their potential to synergize with up-coming treatments and, finally, discusses the challenges and optimism facing this strategy.

scholarly journals The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 207 ◽  
Author(s):  
Jessica Michie ◽  
Conor J. Kearney ◽  
Edwin D. Hawkins ◽  
John Silke ◽  
Jane Oliaro
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Tumour Progression ◽  
Mitochondrial Protein ◽  
Immune Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Inhibitor Of Apoptosis ◽  
T Cell Therapy ◽  
Apoptosis Protein ◽  
Smac Mimetics

One of the hallmarks of cancer cells is their ability to evade cell death via apoptosis. The inhibitor of apoptosis proteins (IAPs) are a family of proteins that act to promote cell survival. For this reason, upregulation of IAPs is associated with a number of cancer types as a mechanism of resistance to cell death and chemotherapy. As such, IAPs are considered a promising therapeutic target for cancer treatment, based on the role of IAPs in resistance to apoptosis, tumour progression and poor patient prognosis. The mitochondrial protein smac (second mitochondrial activator of caspases), is an endogenous inhibitor of IAPs, and several small molecule mimetics of smac (smac-mimetics) have been developed in order to antagonise IAPs in cancer cells and restore sensitivity to apoptotic stimuli. However, recent studies have revealed that smac-mimetics have broader effects than was first attributed. It is now understood that they are key regulators of innate immune signalling and have wide reaching immuno-modulatory properties. As such, they are ideal candidates for immunotherapy combinations. Pre-clinically, successful combination therapies incorporating smac-mimetics and oncolytic viruses, as with chimeric antigen receptor (CAR) T cell therapy, have been reported, and clinical trials incorporating smac-mimetics and immune checkpoint blockade are ongoing. Here, the potential of IAP antagonism to enhance immunotherapy strategies for the treatment of cancer will be discussed.

scholarly journals The “ARTS” of Cell Death in Service of Life: How Do We Force Cancer Cells to Commit Suicide?

2021 ◽  
Vol 9 ◽  
Author(s):  
Sarit Larisch
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Novel Therapy ◽  
The Arts ◽  
Wide Range ◽  
Cell Death Program ◽  
Cancerous Cells ◽  
Critical Process ◽  
Cells Death ◽  
Commit Suicide

Every cell in our body contains a “self-destruction” program. This cell death is a critical process allowing replacement of damaged cells with healthy ones to prevent wide range of diseases. When the cell’s death mechanism gets “stuck” and is not activated, cancer can result. In healthy cells there is a balanced system of proteins, some of which activate the normal death mechanism, and some of which inhibit this process. This is like the system of gas and brakes in a car. Researchers have found that cancer cells lack a protein, called ARTS, which is crucial for activating the cells’ death mechanism. The lack of ARTS causes cancer cells to escape death and become “immortal.” Small ARTS-like molecules have been discovered that can penetrate cancerous cells and reactivate the cell death program, effectively making the cancer cells “commit suicide.” We envision that these ARTS-like molecules will provide novel therapy for cancer.

scholarly journals Carboxylate Analogues of Aryl-Urea-Substituted Fatty Acids That Target the Mitochondria in MDA-MB-231 Breast Cancer Cells to Promote Cell Death

ChemMedChem ◽  
2018 ◽  
Vol 13 (10) ◽  
pp. 1036-1043 ◽  
Author(s):  
Nooshin Koolaji ◽  
Tristan Rawling ◽  
Kirsi Bourget ◽  
Michael Murray
Keyword(s):  
Breast Cancer ◽  
Fatty Acids ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Promote Cell Death

scholarly journals IL23-Producing Human Lung Cancer Cells Promote Tumor Growth via Conversion of Innate Lymphoid Cell 1 (ILC1) into ILC3

2019 ◽  
Vol 25 (13) ◽  
pp. 4026-4037 ◽  
Author(s):  
Jaemoon Koh ◽  
Hye Young Kim ◽  
Youngha Lee ◽  
In Kyu Park ◽  
Chang Hyun Kang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Lymphoid Cell ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Innate Lymphoid Cell ◽  
Promote Tumor Growth ◽  
Human Lung Cancer Cells

scholarly journals O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hao Nie ◽  
Haixing Ju ◽  
Jiayi Fan ◽  
Xiaoliu Shi ◽  
Yaxian Cheng ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Development ◽  
Lactate Production ◽  
Phosphoglycerate Kinase ◽  
Tca Cycle ◽  
Human Colon ◽  
Colon Cancers ◽  
The Tca Cycle ◽  
Promote Tumor Growth

AbstractMany cancer cells display enhanced glycolysis and suppressed mitochondrial metabolism. This phenomenon, known as the Warburg effect, is critical for tumor development. However, how cancer cells coordinate glucose metabolism through glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle is largely unknown. We demonstrate here that phosphoglycerate kinase 1 (PGK1), the first ATP-producing enzyme in glycolysis, is reversibly and dynamically modified with O-linked N-acetylglucosamine (O-GlcNAc) at threonine 255 (T255). O-GlcNAcylation activates PGK1 activity to enhance lactate production, and simultaneously induces PGK1 translocation into mitochondria. Inside mitochondria, PGK1 acts as a kinase to inhibit pyruvate dehydrogenase (PDH) complex to reduce oxidative phosphorylation. Blocking T255 O-GlcNAcylation of PGK1 decreases colon cancer cell proliferation, suppresses glycolysis, enhances the TCA cycle, and inhibits tumor growth in xenograft models. Furthermore, PGK1 O-GlcNAcylation levels are elevated in human colon cancers. This study highlights O-GlcNAcylation as an important signal for coordinating glycolysis and the TCA cycle to promote tumorigenesis.

scholarly journals Iron and Cancer

2018 ◽  
Vol 38 (1) ◽  
pp. 97-125 ◽  
Author(s):  
Suzy V. Torti ◽  
David H. Manz ◽  
Bibbin T. Paul ◽  
Nicole Blanchette-Farra ◽  
Frank M. Torti
Keyword(s):  
Cell Death ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Biology ◽  
Experimental Studies ◽  
Epidemiological Studies ◽  
Excess Iron ◽  
Cell Death Pathways ◽  
Dependent Form ◽  
Active Research

This review explores the multifaceted role that iron has in cancer biology. Epidemiological studies have demonstrated an association between excess iron and increased cancer incidence and risk, while experimental studies have implicated iron in cancer initiation, tumor growth, and metastasis. The roles of iron in proliferation, metabolism, and metastasis underpin the association of iron with tumor growth and progression. Cancer cells exhibit an iron-seeking phenotype achieved through dysregulation of iron metabolic proteins. These changes are mediated, at least in part, by oncogenes and tumor suppressors. The dependence of cancer cells on iron has implications in a number of cell death pathways, including ferroptosis, an iron-dependent form of cell death. Uniquely, both iron excess and iron depletion can be utilized in anticancer therapies. Investigating the efficacy of these therapeutic approaches is an area of active research that promises substantial clinical impact.

scholarly journals Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth

Cell Research ◽  
2018 ◽  
Vol 28 (8) ◽  
pp. 862-864 ◽  
Author(s):  
Yi Yang ◽  
Chia-Wei Li ◽  
Li-Chuan Chan ◽  
Yongkun Wei ◽  
Jung-Mao Hsu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cell Killing ◽  
Active Defense ◽  
Promote Tumor Growth ◽  
Defense Function

scholarly journals miR-221/222 promote tumor growth and suppress apoptosis by targeting lncRNA GAS5 in breast cancer

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Yuanyuan Zong ◽  
Yazhou Zhang ◽  
Xichao Sun ◽  
Tao Xu ◽  
Xiankui Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Novel Approach ◽  
Promote Tumor Growth ◽  
Direct Target Gene ◽  
New Perspective ◽  
Cancer Tissues

Abstract MicroRNAs (miRNAs) are 21–23-nucleotide, short, non-coding RNAs that play important roles in virtually all biological pathways in mammals and other multicellular organisms. The association of miR-221 and miR-222 (miR-221/222) for breast cancer is critical, but their detailed roles in its development and progression remain unclear. In the present study, we found that miR-221/222 were consistently up-regulated in breast cancer tissues. We then investigated the molecular mechanisms by which miR-221/222 contributed to breast cancer and identified growth arrest–specific transcript 5 (GAS5) as a direct target gene of miR-221/222. In contrast with the up-regulated expression levels of miR-221/222, GAS5 levels were significantly down-regulated and negatively correlated with miR-221/222 in breast cancer tissues. In addition, we showed that miR-221/222 inhibitors increased cellular apoptosis, miR-221/222 mimics decreased the cell apoptosis in breast cancer cells, and restoration of GAS5 expression attenuated the anti-apoptotic effects of miR-221/222 in breast cancer cells, indicating that GAS5 was a direct mediator of miR-221/222 function. Finally, we showed that miR-221/222 suppressed GAS5 expression significantly and enhanced tumor growth in a mouse model of breast cancer xenografts. The present study highlighted the important role of miR-221/222 as oncomiRs in breast cancer, which inhibited GAS5 translation. These findings may provide a new perspective for the molecular mechanism of breast carcinogenesis and provide a novel approach to the treatment of breast cancer.

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